RasGRP1 opposes proliferative EGFR-SOS1-Ras signals and restricts intestinal epithelial cell growth

Philippe Depeille, Linda M. Henricks, Robert A.H. Van De Ven, Ed Lemmens, Chih Yang Wang, Mary Matli, Zena Werb, Kevin M. Haigis, David Donner, Robert Warren, Jeroen P. Roose

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Abstract

The character of EGFR signals can influence cell fate but mechanistic insights into intestinal EGFR-Ras signalling are limited. Here we show that two distinct Ras nucleotide exchange factors, RasGRP1 and SOS1, lie downstream of EGFR but act in functional opposition. RasGRP1 is expressed in intestinal crypts where it restricts epithelial growth. High RasGRP1 expression in colorectal cancer (CRC) patient samples correlates with a better clinical outcome. Biochemically, we find that RasGRP1 creates a negative feedback loop that limits proliferative EGFR-SOS1-Ras signals in CRC cells. Genetic Rasgrp1 depletion from mice with either an activating mutation in KRas or with aberrant Wnt signalling due to a mutation in Apc resulted in both cases in exacerbated Ras-ERK signalling and cell proliferation. The unexpected opposing cell biological effects of EGFR-RasGRP1 and EGFR-SOS1 signals in the same cell shed light on the intricacy of EGFR-Ras signalling in normal epithelium and carcinoma.

Original languageEnglish
Pages (from-to)804-815
Number of pages12
JournalNature Cell Biology
Volume17
Issue number6
DOIs
Publication statusPublished - Jun 1 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Depeille, P., Henricks, L. M., Van De Ven, R. A. H., Lemmens, E., Wang, C. Y., Matli, M., Werb, Z., Haigis, K. M., Donner, D., Warren, R., & Roose, J. P. (2015). RasGRP1 opposes proliferative EGFR-SOS1-Ras signals and restricts intestinal epithelial cell growth. Nature Cell Biology, 17(6), 804-815. https://doi.org/10.1038/ncb3175